PROJECT SUMMARY/ABSTRACT The main purpose of the proposed study is to address critical gaps in our understanding of the long-term health risks of occupational exposures in the uranium processing industry. Uranium processing workers are exposed to a wide array of uranium compounds from the ore dust. What makes the proposed study relevant to current-day exposure scenarios is the ability to examine effects of radium on brain tissue, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases (PD and AD). Astronauts are exposed to high-LET radiation from galactic cosmic rays which is similar to radiation from high linear energy- transfer (LET) alpha particles, emitted during radium decay. One of the major concerns of the National Atmospheric and Space Administration (NASA) in space missions to Mars is the effect of high-LET radiation on brain tissue and the possibility of cognitive dysfunction and long-term dementia. The uranium processing cohorts provide the closest human analogue to the circumstances in deep space. Only a few studies have examined mortality risks among uranium processing workers and only two conducted dose-response analyses of North American workers, necessitating further research in this area. We propose to combine the data from these two studies (Fernald Feed Materials Production Center and Port Hope radium and uranium conversion facility) with the recently updated cohort of workers from the Mallinckrodt Chemical Works plant. The exposure and cohort files for the fourth facility, Middlesex Sampling Plant, recently became available and we will use the previously developed methods to estimate individual doses for this cohort. Main analyses will be based on the pooled cohort of ~11,200 men, but we will also conduct exploratory analyses of ~1,500 women involved in uranium processing. Analyses will be conducted for mortality and morbidity outcomes in site-specific organs affected by uranium compounds, including cancers of the lung and bronchi, kidneys, leukaemia and lymphoma, as well as cardiovascular, renal and non-malignant respiratory diseases, AD, PD and dementia. The proposed pooled analysis will be the largest study to date to examine health risks in this group of workers and will guide the development of a new line of research ? before new and more costly studies are undertaken. The proposed study will address two NORA sectors: Manufacturing and Mining, and contribute to three Cross-Sector Programs: Cancer, Reproductive and Cardiovascular Diseases; Respiratory Health; and TOTAL WORKER HEALTH? Program. Our research will contribute to the Core and Specialty Programs, in particular Health Hazard Evaluation (HHE) Program. Expected Outcomes and Outputs: Study findings will provide important and previously unavailable scientific evidence to inform workplace occupational safety regulations in the nuclear fuel production industry. The proposed study has a direct Research to Practice (r2p) component by providing direct estimates of occupational risks of uranium processing workers and an opportunity to investigate the effects of internal dose to the brain from long-term space travel to Mars, of interest to NASA.